Breast cancer survivors face dual challenges: 1) risk of recurrent disease and 2) dealing with the long term sequelae of their treatments. Facing these challenges can be burdensome, resulting in reduced quality of life. Obesity and sedentary lifestyle further complicate these issues. The goal ofthe WISER Survivor trial is to assess the effects of exercise and/or weight loss through caloric restriction on a common long term adverse effect of treatment (lymphedema), biomarkers for recurrence, and quality of life. Lymphedema is a chronic, progressive, incurable condition characterized by arm swelling and negative alterations in function and appearance, as well as bothersome symptoms. It is among the more common, expensive, and feared persistent adverse breast cancer treatment effects. In our completed work, twice weekly weight-lifting reduced by half the number of incident clinical lymphedema events requiring medical care. In the proposed WISER Survivor trial we seek to assess whether adding aerobic exercise or weight loss through caloric restriction to the weight-lifting intervention further improves lymphedema clinical outcomes. The WISER Survivor Trial will also test the effects ofthe exercise and weight loss interventions on the same recurrence biomarkers to be tested in the mouse model study (Project 1). The biomarkers include sex hormones, markers of inflammation, growth factors, adipokines, and oxidative stress. The innovation of these two paired projects include the novel approach of assessing effects of these interventions in the recurrence setting, as well as comparing effects on biomarkers in equivalent interventions in mice and humans. In addition, we assess effects of our energy balance interventions on a novel biomarker related to pathogenic angiogenesis. Another innovation includes a unique opportunity to assess whether changes in any of these biomarkers are correlated with clinical lymphedema outcomes. Finally, we seek to assess effects of our interventions on quality of life in breast cancer survivors with lymphedema. Therefore, we propose a one year randomized controlled weight loss and exercise intervention trial in a multi-ethnic cohort of oven/veight and obese post-menopausal breast cancer survivors with clinically confirmed lymphedema. There will be four groups in this trial: exercise only, weight loss only, exercise and weight-loss combined, and a control group, with a sample size of 125 per group (total N=500).